Modulating the function of ATP-binding cassette subfamily G member 2 (ABCG2) with inhibitor cabozantinib.
Modulating the function of ATP-binding cassette subfamily G member 2 (ABCG2) with inhibitor cabozantinib.
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DOI：
10.1016/j.phrs.2017.01.024
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发表时间：
2017-05
影响因子：
9.3
通讯作者：
Chen ZS
中科院分区：
文献类型：
--
作者：
Zhang GN;Zhang YK;Wang YJ;Barbuti AM;Zhu XJ;Yu XY;Wen AW;Wurpel JND;Chen ZS
卡博替尼（XL 184）是一种小分子酪氨酸激酶受体抑制剂，靶向c-Met和VEGFR 2。卡博替尼已被美国食品和药物管理局批准用于治疗晚期甲状腺髓样癌和肾细胞癌。在本研究中，我们评估了卡博替尼通过致敏对ABCG 2底物药物具有抗性的细胞来调节ATP结合盒亚家族G成员2（ABCG 2）的功能的能力。我们使用了一种药物选择的耐药细胞系H460/MX20和三种ABCG 2稳定转染的细胞系ABCG 2 -482-R2、ABCG 2 -482-G2和ABCG 2 -482-T7，它们过表达ABCG 2。卡博替尼在无毒浓度（3或5 μM）下使ABCG 2过表达细胞对米托蒽醌、SN-38和托泊替康敏感。我们的研究结果表明，卡博替尼通过拮抗ABCG 2转运蛋白的药物外排功能而不是下调其表达来逆转ABCG 2介导的多药耐药。分子对接分析表明，卡博替尼与ABCG 2转运蛋白的药物结合位点结合。总的来说，我们的研究结果表明，卡博替尼抑制ABCG 2转运蛋白功能，从而增强作为ABCG 2底物的抑制剂的作用。卡博替尼可能是对ABCG 2底物药物耐药的患者的抗癌治疗方案中的有用药剂。
Cabozantinib (XL184) is a small molecule tyrosine kinase receptor inhibitor, which targets c-Met and VEGFR2. Cabozantinib has been approved by the Food and Drug Administration to treat advanced medullary thyroid cancer and renal cell carcinoma. In the present study, we evaluated the ability of cabozantinib to modulate the function of the ATP-binding cassette subfamily G member 2 (ABCG2) by sensitizing cells that are resistant to ABCG2 substrate antineoplastic drugs. We used a drug-selected resistant cell line H460/MX20 and three ABCG2 stable transfected cell lines ABCG2-482-R2, ABCG2-482-G2, and ABCG2-482-T7, which overexpress ABCG2. Cabozantinib, at non-toxic concentrations (3 or 5 μM), sensitized the ABCG2-overexpressing cells to mitoxantrone, SN-38, and topotecan. Our results indicate that cabozantinib reverses ABCG2-mediated multidrug resistance by antagonizing the drug efflux function of the ABCG2 transporter instead of downregulating its expression. The molecular docking analysis indicates that cabozantinib binds to the drug-binding site of the ABCG2 transporter. Overall, our findings demonstrate that cabozantinib inhibits the ABCG2 transporter function and consequently enhances the effect of the antineoplastic agents that are substrates of ABCG2. Cabozantinib may be a useful agent in anticancer treatment regimens for patients who are resistant to ABCG2 substrate drugs.